The invention relates to a novel process for preparing by-product-free 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine and to its use as an intermediate in the preparation of herbicidal 7-[(4,6-dimethoxypyrimidin-2-yl)thio]naphthalide derivatives.
Processes for preparing 2-alkylsulfonylpyrimidine derivatives which are disubstituted, in the 4- and 6-position, are already known from EP-A-0 209 779, J. Org. Chem. 26, 792 (1961) and Pestic. Sci. 47, 115 (1996). Some of the processes described proceed in a complicated manner via a plurality of discrete reaction steps, with isolation of the respective intermediates. Thus, for example, the first two documents describe the oxidation to the corresponding 2-alkylsulfonyl-pyrimidine derivatives by introduction of chlorine gas into a two-phase system (Example II-1, page 15) or an absolute alcoholic solution of 2-alkylthiopyrimidine derivatives (example 4,6-dichloro-2-(methylsulfonyl)pyrimidine (compound XXXVII), page 802). Pestic. Sci. describes both the reaction of 4,6-dichloro-2-(alkylthio)-1,3-pyrimidine with sodium alkoxide to the corresponding 4,6-dialkoxy-substituted 2-alkylthio-pyrimidine derivatives and its oxidation to the corresponding 4,6-dialkoxy-2-(alkylsulfonyl)-1,3-pyrimidines with Oxone or hydrogen peroxide and sodium tungstate as catalyst. The pure end product is prepared by recrystallization. However, the observed yields and purities of the products are frequently unsatisfactory for industrial preparation processes. Moreover, the isolation and purification procedures are uneconomical and associated with a high expenditure on apparatus.
It is an object of the present invention to eliminate these disadvantages and to provide a more simple process which is suitable for industrial applications. Surprisingly, it has now been found that 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine can be prepared in a simple manner, in high yield and purity, in an economically and ecologically particularly advantageous manner from 4,6-dichloro-2-(methylthio)-1,3-pyrimidine by reacting the latter compound with an alkali metal methoxide and oxidizing the resulting 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine without isolation directly to the corresponding 2-methylsulfonylpyrimidine derivative and freeing this in a subsequent purification step in the same reaction vessel as a xe2x80x9cone-pot reactionxe2x80x9d from any by-products formed, allowing direct use, for example, for preparing herbicides according to EP-B-0 447 506.
Accordingly, the present invention provides a process for preparing 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine by reacting 4,6-dichloro-2-(methylthio)-1,3-pyrimidine in an inert organic solvent with an alkali metal methoxide, transfer of the resulting 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine into an aqueous-acidic medium and subsequent oxidation of this compound, if appropriate in the presence of a catalyst, wherein the oxidation is followed by a purification step in which the aqueous-acidic reaction mixture is adjusted with aqueous base to a pH in the range of 5-8 and stirred either in the presence or in the absence of an organic solvent.
In the first step (Reaction Scheme 1), the reaction of 4,6-dichloro-2-(methylthio)-1,3-pyrimidine with the alkali metal methoxide is expediently carried out in an inert organic solvent such as a hydrocarbon, for example an aromatic hydrocarbon such as benzene, toluene or the isomeric xylenes, preferably in toluene, at reaction temperatures of from 0xc2x0 C. to the boiling point of the solvent used, preferably at temperatures of from 20xc2x0 to 60xc2x0 C.
The alkali metal methoxide used is preferably sodium methoxide or potassium methoxide and particularly preferably a 30% sodium methoxide solution in methanol or solid sodium methoxide (for example 95%), where from 2 to 3 molar equivalents, preferably from 2.05 to 2.50 molar equivalents, of methoxide are used for the substitution reaction, based on 1 mol of 4,6-dichloro-2-(methylthio)-1,3-pyrimidine. Expediently, the methoxide solution or the solid methoxide is added dropwise or added, respectively, in the temperature range stated within a period of 2-6 hours to a solution of 4,6-dichloro-2-(methylthio)-1,3-pyrimidine which has initially been charged, and the reaction mixture is then stirred for from 5 to 10 hours or until no more starting material can be detected, at temperatures of from 50xc2x0 to 60xc2x0 C.
After this reaction time, the resulting mixture is prepared for the oxidation in the second step. To optimize the product yield, some of the methanol present in the reaction mixture may first be distilled off under reduced pressure, the distillation being terminated once 50-90% of the total amount of methanol has been distilled off. Water and a water-immiscible azeotrope-forming inert organic solvent, for example toluene, are then added to the resulting reaction mixture, and the entire mixture is heated with stirring to from 30xc2x0 to 80xc2x0 C., preferably from 30xc2x0 to 60xc2x0 C. After cooling, the aqueous phase is separated off and, to optimize the yield, once more admixed with the inert organic solvent and heated with stirring to from 30xc2x0 to 80xc2x0 C., preferably from 30xc2x0 to 60xc2x0 C. After cooling, the aqueous phase is separated off and discarded and the two organic phases are combined and substantially evaporated under reduced pressure. Water, heated to from 40xc2x0 to 80xc2x0 C., is added to the resulting residue, and the complete remainder of the organic solvent is distilled off azeotropically, until only water can be detected in the distillate.
The oxidation of the resulting and prepared 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine in the second step (Reaction Scheme 1) is expediently carried out in a protic solvent or a protic solvent mixture and, depending on the oxidizing agent used, if appropriate in the presence of a catalyst. Thus, expediently, a concentrated acid such as a carboxylic acid, for example 100% acetic acid, is added to the prepared aqueous reaction mixture from the first step, until a 1-80%, preferably 2-10%, aqueous solution of the corresponding carboxylic acid is obtained. To this end, depending on the oxidizing agent used, 0.1-0.2 mol % of a catalyst, based on 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine, such as a tungstate, for example sodium tungstate, is added, and this mixture is heated to from 70xc2x0 to 90xc2x0 C., preferably from 75xc2x0 to 80xc2x0 C. From 2 to 4 mol, preferably from 2.1 to 3 mol, of an oxidizing agent, such as a peroxide, for example 20-35% hydrogen peroxide solution, based on 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine, are then added dropwise. The exothermic oxidation reaction is maintained at the stated reaction temperature for 1-6 hours or until all of the methylthiopyrimidine or methylsulfoxide pyrimidine has been oxidized to the methylsulfonylpyrimidine.
After the oxidation has ended, excess oxidizing agent present in the reaction mixture is destroyed in a customary manner, known to the person skilled in the art, for example by adding 40% aqueous sodium hydrogen sulfite solution to the reaction mixture until no more oxidizing agent can be detected (potassium iodide/starch test), and the reaction mixture treated in this manner is prepared for the subsequent purification step which is carried out in the same reaction vessel.
One feature of the reaction sequence according to the invention is the purification step which follows as a xe2x80x9cone-pot reactionxe2x80x9d in the same reaction vessel and which offers great advantages for industrial processes since complicated separation and purification steps can be avoided and the expenditure on apparatus can be reduced.
To this end, the aqueous-acidic reaction mixture obtained in the preceding two-step reaction sequence is first adjusted with an aqueous base at temperatures of from 10xc2x0 to 90xc2x0 C. to a pH in the range from 5-8 and then either according to
Variant A) this resulting aqueous phase is stirred in the temperature range of from 10xc2x0 to 90xc2x0 C. and at the stated pH for from 0.5 to 5 hours, or
Variant B) is admixed with a water-immiscible inert organic solvent such as an aromatic hydrocarbon, for example benzene, toluene or the isomeric xylenes, and the resulting two-phase system is stirred, if appropriate with addition of a phase-transfer catalyst, in the temperature range of from 100 to 90xc2x0 C. and at the stated pH for from 0.5 to 5 hours, or
Variant C) is admixed with a water-miscible organic solvent, for example an alcohol, thus generating an aqueous-organic one-phase system which is stirred in the temperature range from 10xc2x0 to 90xc2x0 C. and at the stated pH for from 0.5 to 5 hours.
During this step, the by-products, formed in an amount of  less than 10%, specifically 2,4-bis(methylsulfonyl)-6-methoxy-1,3-pyrimidine, are hydrolysed to water-soluble by-products, specifically to 2-hydroxy-4-(methylsulfonyl)-6-methoxy-1,3-pyrimidine and 6-hydroxy-2-(methylsulfonyl)-4-methoxy-1,3-pyrimidine, the decrease and increase of which over time in the organic phase and in the aqueous phase, respectively, can be monitored directly, for example by GC, HPLC or TLC (Reaction Scheme 2).
A preferred aqueous base is an aqueous solution of a hydroxide, for example an alkali metal hydroxide. Preference is given to using 30% aqueous sodium hydroxide solution. Suitable water-immiscible aromatic hydrocarbons according to Variant B) are in particular toluene, and suitable water-miscible organic solvents according to Variant C) are in particular methanol and ethanol.
In the case of Variant A), after the stirring in aqueous phase (hydrolysis), it is either possible, in a Variant AB), to add a water-immiscible inert organic solvent and, if appropriate, a phase-transfer catalyst as under Variant B), or, in a Variant AC), to add a water-miscible organic solvent, as mentioned under Variant C), for easier product isolation, followed by stirring of the resultant two-phase (Variant A)+AB)) or aqueous-organic one-phase system (Variant A)+AC)) for from 5 to 15 minutes and work-up similarly to how it is described under Variant B) and C), respectively.
In the case of the two-phase system according to Variant B) or A)+AB), the aqueous phase is separated off and, for complete extraction of the desired target compound, mixed once more with the same water-immiscible organic solvent as used above, and the entire two-phase system is stirred for from 5 to 15 minutes. After cooling, the aqueous phase is separated off, the two organic phases are combined and the organic solvent is distilled off under reduced pressure. Reaction Scheme 2 illustrates this enrichment process (Variants B) and A)+AB)).
Suitable phase-transfer catalysts for Variants B) and A)+AB) are, for example, the catalysts listed in Angew. Chem., Int. Ed. Engl. 13, 170-179 (1974), in particular quaternary ammonium salts, for example tetraalkylammonium halides, and in particular tricaprylmethylammonium chloride (Aliquat 336). The phase-transfer catalysts accelerate the hydrolysis of the by-products and, as solubilizers, increase the dissolution efficiency of these hydrolysed by-products in the aqueous phase. The phase-transfer catalysts are employed in amounts of from 0.1 to 10 mol %, based on the product, 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine.
According to Variant C) and A)+AC), the desired target compound is present as a suspension which is poorly water-soluble and can be separated off easily from the aqueous-organic phase by filtration, whereas the hydrolysed and water-soluble by-products, for example 2-hydroxy-4-(methylsulfonyl)-6-methoxy- and 6-hydroxy-2-(methylsulfonyl)-4-methoxy-1,3-pyrimidine, remain in solution.
Reaction Scheme 2 illustrates this enrichment process (Variants C) and A)+AC)).
To optimize the product yield, in Variant C) and AC), the proportion of water-miscible organic solvents added is kept just at such a level that, on the one hand, homogeneity of the reaction mixture is ensured and, on the other hand, yield losses are as low as possible. In general, the proportion of water-miscible solvents is in the range from 5 to 50% by weight, based on the amount of aqueous-acidic reaction mixture. If the concentration of water-miscible organic solvents is too high, the solubility of the target compound in the aqueous medium is increased, resulting in a reduced product yield.
In preferred Variants A), B) or C), the aqueous base used is, for example, a hydroxide, for example an alkali metal hydroxide, which is added dropwise with stirring at reaction temperatures of from 10xc2x0 to 90xc2x0 C. to the aqueous-acidic reaction mixture until the pH range of the reaction mixture is 5-8, and these resulting mixtures are then stirred in the temperature range and the pH range stated above for from 0.5 to 5 hours, according to Variant A) without addition of an organic solvent, according to Variant B) after addition of an organic solvent, for example an aromatic hydrocarbon, for example benzene, toluene or the isomeric xylenes, or according to Variant C) after addition of an organic solvent, for example an alcohol. Among these, preference is given to those variants in which the aqueous base used is a 30% aqueous sodium hydroxide solution, which is added dropwise at reaction temperatures of from 75xc2x0 to 85xc2x0 C. to the aqueous-acidic reaction mixture until the pH is 6-7, where either no organic solvent (Variant A)) or the organic solvent toluene (Variant B)) or methanol or ethanol (Variant C)) is added, and these mixtures are stirred in the temperature range of from 20xc2x0 to 80xc2x0 C. and in the pH range stated above for from 1 to 3 hours.
In a particularly preferred Variant B), the organic water-immiscible solvent which is added to the aqueous reaction mixture is toluene, employing, as phase-transfer catalyst, tricaprylmethylammonium chloride (Aliquat 336) in an amount of from 0.5 to 5 mol %, based on the 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine formed.
The intermediate 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine (not isolated, Reaction Scheme 1) is chemically stable and could be isolated without any problems from the reaction mixture.
Accordingly, as an alternative to the present process with an initial two-step reaction sequence for the preparation of 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine starting from 4,6-dichloro-2-(methylthio)-1,3-pyrimidine, it is also possible to use an initial one-step process in which the starting material 4,6-dimethoxyl-2-(methylthio)-1,3-pyrimidine is oxidized in an aqueous-acidic medium, if appropriate in the presence of a catalyst, wherein a purification step according to the present invention is carried out after the oxidation. The present invention also provides this alternative process. 
The overall yields of isolated product 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine are generally  greater than 75%, the purity of the end product being  greater than 98%.
The starting material 4,6-dichloro-2-(methylthio)-1,3-pyrimidine is known, for example, from J. Org. Chem. 26, 792 (1961). Likewise known are all of the reagents used, such as methoxides, oxidizing agents and phase-transfer catalysts, or they can be prepared by known processes.
The process according to the invention differs from the known processes in that
1) it affords the target compound 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine in high purity and yield,
2) it can be carried out in a multipurpose plant,
3) it can be carried out both continuously and batch-wise (discontinuously),
4) with respect to Step 2 (oxidation) and the purification step, it is designed as a xe2x80x9cone-pot reactionxe2x80x9d,
5) it does not require a complicated recrystallization, which is associated with product loss,
6) it provides easy direct access, in an economically and ecologically advantageous manner, to 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine, and
7) it permits subsequent reactions xe2x80x9cin situxe2x80x9d, for example conversion into 7-[(4,6-dimethoxypyrimidin-2-yl)thio]phthalide derivatives.
Accordingly, compared to the known processes, the present process has the following advantages:
1) it is particularly suitable for industrial processes,
2) it avoids complicated separation and purification steps,
3) it allows easy recycling of organic solvents (for example toluene and methanol) and/or avoids problematic waste (only water and salts, for example sodium chloride and sodium sulfate and/or sodium acetate are produced), and
4) it allows direct xe2x80x9cin situxe2x80x9d further processing of the 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine formed.
The 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine prepared according to the invention is an important intermediate in the synthesis of herbicides and is used specifically as an intermediate in the preparation of herbicidal 7-[(4,6-dimethoxypyrimidin-2-yl)thio]-3-methylnaphthalide, as described, for example, in EP-B-0 447 506 and as illustrated in Reaction Scheme 1. 
The starting material used is 4,6-dichloro-2-(methylthio)-1,3-pyrimidine which, according to Reaction Scheme 1 and as described above, is reacted in the first step in an inert organic solvent with an alkali metal methoxide to give the 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine intermediate, which is not isolated, the inert organic solvent is replaced by an aqueous-protic solvent, and, in a second step, the corresponding 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine is obtained in pure form by oxidation and a subsequent purification step designed as xe2x80x9cone-pot reactionxe2x80x9d. The subsequent reaction of the 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine formed with 7-mercapto-3-methylnaphthalide in Reaction Scheme 1 is expediently carried out in an inert organic solvent, for example alcohols, ethers, ketones, nitrites or amides, for example isopropanol, tetrahydrofuran, butanone, acetonitrile or N,N-dimethylformamide, at temperatures of from 0xc2x0 to 160xc2x0 C. Such substitution reactions are described, for example, in EP-B-0 447 506.
The process according to the invention is illustrated in more detail by the example below.